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Dual roles of Nell-1 in craniofacial bones and brain through interaction with Cntnap4

Nell-1 通过与 Cntnap4 相互作用在颅面骨和大脑中发挥双重作用

基本信息

批准号：
10450876
负责人：
Chia Soo
金额：
$ 46.54万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450876
关键词：
Adult Agonist Behavior Behavior assessment Behavioral Binding Bone Growth Bone Regeneration Brain Calvaria Cell surface Cells Cephalic Craniosynostosis Data Defect Development Drug or chemical Tissue Distribution Embryo Ethylnitrosourea Event Exhibits Fiber Frontal bone structure GABA Agonists Goals Growth and Development function Histology Human Integrins Interneurons Intervention Knock-out Knockout Mice Knowledge Ligands Link LoxP-flanked allele Measurement Mediating Membrane Proteins Molecular Morphology Mus Mutant Strains Mice Natural regeneration Neonatal Nervous system structure Neural Crest Cell Neurons Osteoblasts Osteogenesis Outcome Output Parietal bone structure Parvalbumins Pathogenesis Patients Phosphorylation Process Property Proteins Role Sensory Ganglia Signal Transduction Skeletal Development Skeletal system Specific qualifier value Structure of trigeminal ganglion Surgical sutures Synaptic Membranes Synaptic Transmission Testing Therapeutic Tissues Transgenic Organisms Translating WNT Signaling Pathway Wild Type Mouse autism spectrum disorder beta catenin bone bone healing bone repair brain tissue comparative craniofacial craniofacial bone gamma-Aminobutyric Acid glycogen synthase kinase 3 beta healing improved inhibitor member microCT neurological pathology novel novel therapeutics osteogenic osteogenic protein overexpression postnatal premature presynaptic receptor relating to nervous system repaired skeletal skeletal tissue spatiotemporal transmission process

项目摘要

PROJECT SUMMARY Nell-1 has been studied extensively for its osteogenic role in craniofacial skeletal development. However, despite its high expression in the brain, there has been a lack of understanding of Nell-1's function in the nervous system until the recent identification of a ligand-receptor like interaction between Nell-1 and Cntnap4. Cntnap4 is a pre- synaptic membrane protein whereby global Cntnap4 loss differentially inhibits GABAergic output and augments dopaminergic transmission, and can induce autism spectrum disorder (ASD)-like behaviors in mice. Remarkably, ENU-induced Nell-1 haploinsufficient mice exhibit ASD-like behaviors similar to those seen in Cntnap4 mutant mice. Meanwhile, inactivation of either Cntnap4 or Nell-1 in cranial neural crest cells (CNCCs) gives rise to remarkably similar calvarial bone defects. Moreover, novel co-localization studies of Nell-1 and Cntnap4 in mouse and human brains revealed broad neural tissue distribution and high levels of co-localized expression. Consequently, this proposal hypothesizes that Nell-1 has dual roles in the brain and craniofacial bones (CB) via a novel interaction between Nell-1 and Cntnap4, and that disruption of the Nell-1/Cntnap4 functional axis will not only induce deficits in CB, but also interfere with neural transmission in the brain. This proposal advances three specific aims to investigate the Nell-1/Cntnap4 functional axis in the CB and brain using two new floxed mouse lines, Nell-1fl/fl and Cntnap4fl/fl. AIM 1 will first define the tissue distribution and expression of Nell-1 and Cntnap4 in both the CB and brain during normal development and growth in wild type (WT) mice. AIM 1 will then specify the functional contributions of Nell-1 and Cntnap4 to the CB and brain using tissue-specific knockout (KO) Nell- 1Wnt1KO and Cntnap4Wnt1KO mice targeting CNCCs-derived CB and trigeminal ganglions (TG) by Wnt1-Cre, and Nell-1PV-2AKO and Cntnap4PV-2AKO mice targeting parvalbumin positive (PV+) GABAergic neurons in the brain and TG by PV-2A-Cre. The CB growth and behavioral changes in these KO mice will be correlated with morphological changes in the examined bones, brain, and the craniofacial neuroskeletal interface where TG sensory fibers innervate the CB. AIM 2 will decipher Nell-1's osteogenic property in the context of Cntnap4 during the repair and regeneration of CB defects in Cntnap4Wnt1KO mice using Nell-1 protein. With Nell-1 serving as an agonist of Wnt/β-catenin signaling, AIM 2 will determine how integrin β1, a Nell-1 binding partner, and glycogen synthase kinase-3β (GSK3β), a crucial regulator of β-catenin phosphorylation, modulate Nell-1/Cntnap4 interaction-mediated Wnt/β-catenin signaling activation during CNCC osteogenesis. AIM 3 will investigate Nell- 1/Cntnap4 interaction on brain GABAergic transmission and ASD-like behaviors in Nell-1PV-2AKO and Cntnap4PV- 2AKO mice. AIM 3 will further assess Wnt/β-catenin signaling in the context of Nell-1/Cntnap4 interaction- mediated GABA release, along with the possible additive or synergistic effects of GSK3β inhibitors with Nell-1 in mouse neuronal cells. IMPACT: The ultimate goal is to reveal how the newly identified Nell-1/Cntnap4 interaction may translate into developing Nell-1 as a novel therapeutic to treat human skeletal and neurological pathologies.

项目总结